For the last three years we have studied plasma GABA in normal controls and in patients with mood disorders. Our findings to date suggest that plasma GABA levels are stable over time in both controls and patients, and not affected by season, time of day, gender, age, menstrual status, diet, cholinergic challenge, or mild exercise. Plasma GABA in patients with primary unipolar depression are significantly lower than in control, particularly in a subset (40%) of patients. These findings suggest that plasma GABA may have some characteristics of a stable trait-like marker. This hypothesis will be tested in the following proposal in two experiments. First, a number of patients in remission off medication will be studied to determine whether the low plasma GABA seen in some of them, while symptomatic, reverts to normal with time. Second, siblings of patients with low GABA will be studied to investigate whether there is a familial association between low plasma GABA and mood disorder. These experiments should provide additional data regarding the role of plasma GABA in depression, and whether the subset of patients with low GABA share distinct clinical features. The work proposed should further our understanding of the biochemistry of mental illness.